Processing of the Amyloid Protein Precursor to Potentially Amyloidogenic Derivatives

Abstract

The approximately 120-kilodalton amyloid beta protein precursor (beta APP) is processed into a complex set of 8- to 12-kilodalton carboxyl-terminal derivatives that includes potentially amyloidogenic forms with the approximately 4-kilodalton amyloid beta protein (beta AP) at or near their amino terminus. In order to determine if these derivatives are processed in a secretory pathway or by the endosomal-lysosomal system, (i) deletion mutants that produce the normal set of carboxyl-terminal derivatives and shortened secreted derivatives were analyzed and (ii) the effect of inhibitors of endosomal-lysosomal processing was examined. In the secretory pathway, cleavage of the beta APP occurs at a single site within the beta AP to generate one secreted derivative and one nonamyloidogenic carboxyl-terminal fragment, whereas, in the endosomal-lysosomal system, a complex set of carboxyl-terminal derivatives is produced that includes the potentially amyloidogenic forms.

An Etiological Role of Amyloidogenic Carboxyl‐Terminal Fragments of the β‐Amyloid Precursor Protein in Alzheimer's Disease

“…The A/I is composed of 39-43 amino acids and proteolytically derived from larger /3-amyloid precursor protein (/3APP) isoforms of 695, 714, 751, and 770 amino acids (Kang et al, 1987). Several mutations of /IAPP around the A/I domain have been discovered in certain types of earlyonset familial AD (FAD) (for review, see Tanzi et al, 1993), supporting its causal role in the pathogenesis of AD.To date, at least three processing pathways have been described: the nonamyloidogenic secretory pathway (a-secretase), which releases soluble ectodomain and prevents A/I formation (Esch et al, 1990); the endosomal-lysosomal pathway, in which some cell surface /IAPPs are reinternalized (Haass et al, 1 992a,b) and cleaved around at the N-terminus of the A/I sequence by /3-secretase to produce A/3-bearing amyloidogenic breakdown products of various sizes (14-22 kDa) Golde et al, 1992; Haass et al, 1992a,b;Shoji et al, 1992;Tamaoka et al, 1992) and subsequently possibly cleaved by 'ysecretase to release soluble 4-kDa A/I (Koo and Squazzo, 1994); and the 4-kDa A/I-producing pathway (/3-and y-secretases), involving coated pit-mediated endocytosis, which may be independent of the constitutive secretory pathway (Koo and Squazzo, 1994).Classically, A/I is the marker for AD, and it has been linked to the accompanying neurodegeneration (see, e.g., Sisodia et al, 1990). Several lines of evidence suggest that the overexpression of /3APP and the subsequent production of A/I could be linked to the genesis of AD (for review, see Checler, 1995).…”

“…The recent concentration on other potentially amyloidogenic products of /IAPP has produced interesting candidates, the most promising of which are the amyloidogenic carboxyl-terminal (CT) fragments of /IAPP. The transgenic mice expressing /IAPP and presenilins were not, however, examined for the presence of CT 100.First, CT peptides have been found not only in various cultured cells (Maruyama et al, 1990;Wolf et al, 1990;Dyrks et al, 1992;Estus et al, 1992; Gandy et al., 1992a,b;Golde et al, 1992;Haass et al, 1992b) but also in paired helical filaments (Caputo et al, 1992), in senile plaques (Selkoe et al, 1988), in microvessels (Tamaoka et al, 1992), and in choroid plexus from human brain in AD, in the white matter of Down's syndrome brains (Tokuda et al, 1995), and in human platelets (Tables 1 and 2). CT fragments with molecular masses of 12-16 kDa have also been found in media and cytosol of lymphoblastoid cells obtained from patients with earlyor late-onset FAD (Matsumoto, 1994) and Down's syndrome (Kametani et al, 1994).…”

“…To date, at least three processing pathways have been described: the nonamyloidogenic secretory pathway (a-secretase), which releases soluble ectodomain and prevents A/I formation (Esch et al, 1990); the endosomal-lysosomal pathway, in which some cell surface /IAPPs are reinternalized (Haass et al, 1 992a,b) and cleaved around at the N-terminus of the A/I sequence by /3-secretase to produce A/3-bearing amyloidogenic breakdown products of various sizes (14-22 kDa) Golde et al, 1992; Haass et al, 1992a,b;Shoji et al, 1992;Tamaoka et al, 1992) and subsequently possibly cleaved by 'ysecretase to release soluble 4-kDa A/I (Koo and Squazzo, 1994); and the 4-kDa A/I-producing pathway (/3-and y-secretases), involving coated pit-mediated endocytosis, which may be independent of the constitutive secretory pathway (Koo and Squazzo, 1994).…”

A mechanism for β‐amyloid overproduction in Alzheimer's disease: precursor‐independent generation of β‐amyloid via antisense RNA‐primed mRNA synthesis

“…AI~ can be produced by proteolysis of pAPP, a process that occurs constitutively in both normal and AD-affected tissues as well as in cultured cells [8][9][10][11][12], and its overproduction in AD is currently explained in terms of proteolytic processing of I~APP. pAPP proteolysis is effected by yet to be identified enzymes designated t~-, [~-and y-secretases ( Fig.…”

The Decrement of Muscarinic Receptor-Mediated Calcium Influx by Overexpression of APP in a Mouse Cholinergic Cell Line.

“…This results suggests adenylate cyclase activity may be down-regulated in SN49MA but this may not be related to APP overexpression itself, because SN49PX also reduced its cAMP content in the similar extent. Findings from these experiments show (i) APP may have neurite-promoting properties and acts as a neuroprotective molecule that can down-regulate intracellular calcium levels in cultured rat and human neurons (Mattson et al 1993b) and (ii) secreted fAP and probably intracellular amyloidogenic APP C-terminal fragments, which are present as membrane bound form Golde et al 1992), may be neurotoxic by disturbing calcium homeostasis (Mattson et al 1993a). Moreover, several reports suggest the properties of APP derivatives are closely related to Ca2+ and K+ ion channels Lahiri et al 1992;Nitsch et al 1992;Arispe et al 1993;Etcheberrigaray et al 1994;Weiss et al 1994).…”